Abstract
BackgroundRadiotherapy (RT) is the primary treatment modality for inoperable, locally advanced non-small-cell lung cancer (NSCLC), but even with highly conformal treatment planning, radiation pneumonitis (RP) remains the most serious, dose-limiting complication. Previous clinical reports proposed that cytokine plasma levels measured during RT allow to estimate the individual risk of patients to develop RP. The identification of such cytokine risk profiles would facilitate tailoring radiotherapy to maximize treatment efficacy and to minimize radiation toxicity. However, cytokines are produced not only in normal lung tissue after irradiation, but are also over-expressed in tumour cells of NSCLC specimens. This tumour-derived cytokine production may influence circulating plasma levels in NSCLC patients. The aim of the present study was to investigate the prognostic value of TNF-α, IL-1β, IL-6 and TGF-β1 plasma levels to predict radiation pneumonitis and to evaluate the impact of tumour-derived cytokine production on circulating plasma levels in patients irradiated for NSCLC.Methodology/Principal FindingsIn 52 NSCLC patients (stage I–III) cytokine plasma levels were investigated by ELISA before and weekly during RT, during follow-up (1/3/6/9 months after RT), and at the onset of RP. Tumour biopsies were immunohistochemically stained for IL-6 and TGF-β1, and immunoreactivity was quantified (grade 1–4). RP was evaluated according to LENT-SOMA scale. Tumour response was assessed according to RECIST criteria by chest-CT during follow-up. In our clinical study 21 out of 52 patients developed RP (grade I/II/III/IV: 11/3/6/1 patients). Unexpectedly, cytokine plasma levels measured before and during RT did not correlate with RP incidence. In most patients IL-6 and TGF-β1 plasma levels were already elevated before RT and correlated significantly with the IL-6 and TGF-β1 production in corresponding tumour biopsies. Moreover, IL-6 and TGF-β1 plasma levels measured during follow-up were significantly associated with the individual tumour responses of these patients.Conclusions/SignificanceThe results of this study did not confirm that cytokine plasma levels, neither their absolute nor any relative values, may identify patients at risk for RP. In contrast, the clear correlations of IL-6 and TGF-β1 plasma levels with the cytokine production in corresponding tumour biopsies and with the individual tumour responses suggest that the tumour is the major source of circulating cytokines in patients receiving RT for advanced NSCLC.
Highlights
Radiotherapy (RT) is the most important treatment modality for inoperable, locally advanced non-small-cell lung cancer (NSCLC), but conventional RT with doses in the range of 60– 70 Gy is often insufficient to eradicate the tumour, with local control rates of only 10–20% at one year [1,2]
The increased production of cytokines in tumour tissues which is launched into the blood circulation suggests the possibility of using cytokine plasma levels as tumour markers to monitor the disease course
In most of the 21 patients suffering lung toxicity, IL-6 and TGF-b1 plasma levels measured at the onset of radiation pneumonitis (RP) were increased compared to their individual pre-RT values. This observation may indicate that the inflammatory process of radiation-induced lung injury is associated with an increased production of IL-6 and TGF-b1 within the irradiation field, which is launched into the blood circulation leading to elevated plasma levels
Summary
Radiotherapy (RT) is the most important treatment modality for inoperable, locally advanced non-small-cell lung cancer (NSCLC), but conventional RT with doses in the range of 60– 70 Gy is often insufficient to eradicate the tumour, with local control rates of only 10–20% at one year [1,2]. Radiotherapy (RT) is the primary treatment modality for inoperable, locally advanced non-small-cell lung cancer (NSCLC), but even with highly conformal treatment planning, radiation pneumonitis (RP) remains the most serious, dose-limiting complication. Previous clinical reports proposed that cytokine plasma levels measured during RT allow to estimate the individual risk of patients to develop RP. The identification of such cytokine risk profiles would facilitate tailoring radiotherapy to maximize treatment efficacy and to minimize radiation toxicity. Cytokines are produced in normal lung tissue after irradiation, but are over-expressed in tumour cells of NSCLC specimens This tumour-derived cytokine production may influence circulating plasma levels in NSCLC patients. The aim of the present study was to investigate the prognostic value of TNF-a, IL-1b, IL-6 and TGF-b1 plasma levels to predict radiation pneumonitis and to evaluate the impact of tumour-derived cytokine production on circulating plasma levels in patients irradiated for NSCLC
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